Dose:     20 mg/kg IV, PO as loading dose
               5 to 10 mg/kg/dose as maintenance dose

Frequency: Q day

Comments: Caffeine citrate is a methylxanthine derivative used to treat apnea of prematurity and apnea following general anesthesia in ex-premature infants. Caffeine is rapidly and completely absorbed from the GI tract with peak serum levels reached in 30 to 120 min. Plasma and CSF concentrations are nearly identical. Infants who fail to respond to the initial recommended dosages, may respond to an increased dose, though no additional clinical benefit has been noted once serum levels have exceeded 25 mcg/ml. Care must be taken in adjusting the dose as caffeine has an extremely slow elimination rate in premature infants. The time required to reach a new steady-state level may exceed two weeks after changing the maintenance dose, though this appears to change as infants become older. Because of its long half-life, caffeine levels need to be followed less frequently than theophylline levels. A meta-analysis of published studies of caffeine versus theophylline for the treatment of apnea by Henderson-Smart and Steer confirmed the advantages of caffeine over theophylline (a higher therapeutic ratio, more reliable enteral absorption, and a longer half-life).

The results of a large, multi-center, randomized trial using caffeine to treat apnea of prematurity were recently published. The first (Schmidt. NEJM 2006; 354:2112-2122) found that use of caffeine (starting in the first few days of life in infants 500 to 1250 grams and continued to around 35 weeks PCA) was associated with a decrease in the incidence of BPD (oxygen use at 36 weeks) of 47% in the placebo-treated group to 36% in the caffeine-treated group. This was thought to be due to a decrease in the length of time positive pressure support was needed (one week less). Caffeine use was associated with a decrease in weight gain during the first 3 weeks of life but not in the following six weeks. There was no increase in the incidence of NEC, ROP, IVH, or death in caffeine-treated infants. Analysis of other outcomes after completion of the initial trial showed a marked decrease in the number of infants who required treatment for a PDAs (12.6% in placebo group to 4.5% in caffeine-treated group). In addition, the use of RBC transfusions, post-natal steroids, and doxapram were decreased in the caffeine-treated group. The second paper which looked at long-term outcomes (Schmidt. NEJM 2007; 357:1893-1902) reported that infants in the caffeine treated group had an improved rate of survival without neurodevelopmental disability at 18 to 21 months (decreased incidence of CP from 7.3% to 4.4%-most cases were mild-and cognitive delay). The rates of death, blindness, deafness, and growth parameters were similar. Data are currently continuing to be collected for evaluation of outcomes at 5 years.

A meta-analysis was reported by Henderson-Smart and Steer on the use of caffeine in ex-preterm infants (40 to 44 weeks PCA) who undergo general anesthesia for surgery. The prophylactic use of caffeine (either 5 mg/kg or 10 mg/kg) has been shown to prevent episodes of apnea, cyanosis and bradycardia during the postoperative period without clinically important side effects. However, because of the small numbers of infants studied in these trials and uncertainty concerning the clinical significance of the episodes, caution is warranted in applying these results to routine clinical practice. Further comments on caffeine.

Toxicity: There are few long-term studies to evaluate the safety of caffeine for treatment of apnea. With an acute overdose, symptoms may be seen with serum levels as low as 40 to 50 mcg/ml. These symptoms are: tachypnea, fine tremors, opisthotonus, and tonic-clonic movements. Schmidt (NEJM 2006; 354:2112-2122) reported these to be infrequent using the above dosing recommendations. Though the FDA required a warning of a possible association of NEC with use of caffeine, an increased incidence of NEC associated with caffeine use was not seen in Schmidt's study. Following a chronic overdose, jitteriness has been reported with levels exceeding 50 mcg/ml, though some have not noted any symptoms below 100 mcg/ml. Significant symptoms are usually not seen unless serum concentrations reach 100 to 200 mcg/ml. These levels of caffeine have been associated with tachycardia (200-260 beats/min) and mild glycosuria. Davis (Arch Dis Child 1986; 61:791) reported seizures in two infants who were started on caffeine after an ALTE event, both at several months of age. The seizures were thought in retrospect to have caused the ALTE and the caffeine was thought to have lowered the seizure threshold in these two infants.

Preparation:
IV: Caffeine citrate injection (Cafcit) is supplied in a 3 ml preservative-free solution with a 20 mg/ml concentration. The pharmacy will prepare a unit dose with the exact dose contained in the syringe. Infuse loading dose over 30 minutes and maintenance dose over 15 to 20 minutes (infusion policy). Store at room temperature. The solution is colorless. For single use only.

PO: A very expensive oral preparation of caffeine citrate is now available in a 20 mg/ml concentration (Cafcit). When discontinuing IV caffeine and starting oral dosing, use 09:00 as the standard once a day dosing time.

In the past, an extemporaneous preparation was made by the dissolution of 600 mg caffeine citrate in 30 ml sterile water for irrigation. Filter through 5 micron filter into one ounce amber bottle. Refrigerate. (mOsm = 93) Missouri state law prohibits the use of extemporaneously prepared medications when manufactured formulations are available.